SUMMARY Several lines of evidence suggest that tetracycline antibiotics, such as minocycline and doxycycline, are a promising new avenue to explore for prevention and treatment of schizophrenia. Tetracycline presumably targets increased synapse elimination by microglia underlying schizophrenia. This is the first strategy based on disease mechanism that is uncovered by preclinical studies, including the largest genetic and transcriptomic studies, as well as state-of-the-art stemcell-based technologies. It can therefore be viewed as the first pay-off of the tremendous efforts made by the global genomics consortia to generate novel leads to understand and treat schizophrenia. Over the last decades, multiple small clinical trials have been performed to test potential efficacy of new drugs for prevention and treatment of schizophrenia. Most of these trials failed or could not be replicated, perhaps because of a limited scientific premise. Here we suggest building better evidence for the potential efficacy of tetracycline antibiotics before performing large clinical trials. We will use one of the largest datasets in the world for which both detailed information of tetracycline exposure is available for all individuals in Denmark, as well as information on schizophrenia spectrum disorders diagnosed in all psychiatric treatment settings. The longitudinal nature of the data sources, and the length and extent of the follow-up of the subjects, is unique and unprecedented: 25 years follow-up period provides the opportunity to investigate whether the exposure to tetracycline antibiotics prevents or delays onset of a schizophrenia spectrum disorder. First, we will analyze the risk of a schizophrenia spectrum disorder after exposure to the brain-penetrant doxycycline. Next, we will look at the role of timing and duration of exposure to these antibiotics. Finally, we will compare the influence of exposure to doxycycline prescribed for acne on schizophrenia risk with exposure to other types of treatments prescribed for acne and to unexposed individuals. We will perform matched cohort studies to compare the exposed group with an unexposed group, or with a group exposed to other types of medication. As confounders we consider sex, socioeconomic status, family history of mental illness, and psychiatric and somatic comorbidity. The outcome of this study will be a better understanding of the utility of tetracycline antibiotics for prevention and treatment of schizophrenia spectrum disorders and will inform the design of a placebo-controlled randomized clinical trial of tetracycline for schizophrenia prevention, with the developmental period and potential dose informed by the results found here.